The present invention relates to an integrated nutrient infusion preparation for total parenteral nutrition (TPN) therapy. By the infusion preparation according to the present invention, an essential fatty acid deficiency can be ameliorated or prevented while supplementing various nutritional components that are biologically required. In addition, an appreciable transparency of the nutrient infusion preparation enables a visual identification of insoluble foreign bodies present in an infusion container as well as administration through a sterilization filter to a patient, whereby a marked advantage is exerted.
A method for supplementing nutrition to a patient who is hospitalized due to a disease or injury has been conventionally an oral administration, which is the most natural and desirable method. However, to a patient for whom it is completely impossible to take nutrition orally for a prolonged period, a TNP solution containing various nutritional components such as saccharides, electrolytes and amino acids is administered generally via the central vein of the patient.
A TPN solution is administered to a patient usually after mixing saccharides, electrolytes and amino acids with each other to obtain the infusion preparation aseptically in a pharmaceutical laboratory in a hospital. Since this mixing procedure for obtaining the infusion preparation is complicated, the infusion preparation is contained in a multi-chamber container in which saccharides, electrolytes and amino acids have previously been filled but the saccharides and the amino acids have been separately filled because of their interaction. The multi-chamber container such as plastic containers having a plurality of chambers have already been developed and marketed for the purpose of saving the effort in the complicated procedure described above as well as preventing an invasion of microorganisms during the mixing procedure.
However, a patient who is administered with only a TPN solution containing various nutritional components such as saccharides, electrolytes and amino acids for a prolonged period will exhibit the symptoms of an essential fatty acid deficiency such as scale efflorescence, eczematoid eruption, retarded wound healing, thrombocytopenia, fat swelling, anemia, susceptibility to infection, increased water intake without increasing urine volume, growth disturbance, impotenia generandi and the like, which are problematic during TPN therapy. In addition, an essential fatty acid deficiency which is rare in a human living a routine life is observed frequently in a patient receiving only transvenous nutrition, and is developed within a period of 4 to 6 weeks especially when an energy source is only saccharides. Such essential fatty acid deficiency can be avoided by administering an essential fatty acid-rich fat emulsion concomitantly during TPN therapy.
It has been believed that the essential fatty acid deficiency can be prevented or ameliorated by daily administration of 50 to 100 mL of a 10% fat emulsion. In clinical practice, 200 to 500 mL of a 10% or 20% fat emulsion are given 2 or 3 times a week (Mascioli et al., Eur. J.Clin. Nutr, 51, 232-242 (1997), Tsukamoto et al., JJPEN, 14, (2) 135-138 (1992), Saito et al., JJPEN, 14 (2), 143(1992), Hiramatsu et al., NIPPON RINSHO, 49 (special edition), 125-129 (1991) , Yoshimoto et al., Medical Practice, 7, 114-122 (1990), A.Tashiro, PEN, 15 (2), 19-21 (1997)).
In a method for administering a fat emulsion during TPN therapy, a TPN solution is mixed directly with a fat emulsion, or a fat emulsion is introduced via a TPN infusion line, or it is injected separately via the peripheral vein.
While the essential fatty acid deficiency can be prevented by combining a TPN solution with a fat emulsion as discussed above, mixing of the fat emulsion with the electrolytes infusion causes an aggregation of particles due to the presence of divalent cations such as calcium ions or magnesium ions in the electrolytes. And mixing of the fat emulsion with amino acids also causes an aggregation of the fat particles due to the presence of basic amino acids such as arginine, lysine or histidine similarly to the above electrolytes. The resultant aggregation of fat, when administered to a living body may cause adverse reactions such as an embolism of a pulmonary capillary vessel. Accordingly, mixing of a TPN solution with a fat emulsion should be carried out carefully, for example, by ensuring consumption within 24 hours.
A commercially available fat emulsion is opaque like milk. As a result, a high TPN solution that is incorporated with the fat emulsion appears opaque even if the amount of the fat emulsion is small. Thus, it is impossible to identify insoluble foreign bodies, if any, in the TPN solution. Accordingly, the United State Food and Drug Administration FDA) recommended on Apr. 18, 1994 that a fat emulsion should be given by a different route entirely from that for an infusion preparation containing saccharides, electrolytes and amino acids.
A TPN solution is administered to a patient generally after filtration through a sterilization filter having a pore size of 0.2 to 0.45 xcexcm in order to prevent contamination with microorganisms. However, it is difficult to filter the fat emulsion to be incorporated in the TPN solution through a sterilization filter having a pore size of 0.2 to 0.45 xcexcm, since it contains fat particles having a mean particle size usually of about 0.200 to 0.300 xcexcm together with rough particles having a size as large as 1.000 xcexcm or greater. Accordingly, there is no option practically but to use a filter having a pore size of 1.2 xcexcm which can filter the fat emulsion before administration in order to remove aggregated fat particles, foreign bodies and large-sized microorganisms such as Candida albicans species.
Because of the above described reasons, it has been difficult to provide a TPN solution containing fat as a single-component product, in spite of the fact that administration of the fat emulsion is effective in preventing an essential fatty acid deficiency during TPN therapy.
In the course of formulating a TPN solution containing a fat emulsion, we discovered, based on the fact that it is necessary to store the fat emulsion, electrolytes and amino acids separately until the time just before use, that the problems discussed above can be solved by storing the fat emulsion, the electrolytes and the amino acids separately in a plurality of chambers in a flexible plastic container and by using a fat emulsion consisting essentially of particles whose mean particle size is smaller than that of a conventional fat emulsion, thus establishing the present invention.
Thus, one embodiment of the present invention is a nutrient infusion preparation comprising a fat emulsion consisting essentially of fat particles having a mean particle size of 0.003 to 0.100 xcexcm and a dispersion medium, and a solution containing electrolytes and/or amino acids. The former emulsion is separated from the latter solution and the emulsion and solution are mixed with each other just before administration to a patient.
Also, another embodiment of the present invention is a nutrient infusion preparation comprising a fat emulsion (A) consisting essentially of fat particles having a mean particle size of 0.003 to 0.100 xcexcm and a dispersion medium, and a solution (B) containing electrolytes and amino acids.
Furthermore, another embodiment of the present invention is a nutrient infusion preparation comprising a fat emulsion (A) consisting essentially of fat particles having a mean particle size of 0.003 to 0.100 xcexcm and a dispersion medium, a solution (B-1) containing electrolytes and a solution (B-2) containing amino acids.
Another embodiment of the present invention is a container for a nutrient infusion preparation which is characterized by having a plurality of chambers isolated from each other by partitions capable of being easily opened, wherein one chamber contains a fat emulsion consisting essentially of fat particles having a mean particle size of 0.003 to 0.100 xcexcm and a dispersion medium, and the other chamber contains a solution containing electrolytes and/or amino acids.
Furthermore, another embodiment of the present invention is a container for a nutrient infusion preparation having a plurality of chambers which are isolated from each other by partitions capable of being easily opened, wherein one chamber contains a fat emulsion (A) consisting essentially of fat particles having a mean particle size of 0.003 to 0.100 xcexcm and a dispersion medium, and the other chamber contains a solution (B) containing electrolytes and amino acids.
Furthermore, a further embodiment of the present invention is a container for a nutrient infusion preparation which is characterized by having a plurality of chambers isolated from each other by partitions capable of being easily opened, wherein one chamber contains a fat emulsion (A) consisting essentially of fat particles having a mean particle size of 0.003 to 0.100 xcexcm and a dispersion medium, and the other chambers respectively contain a solution (B-1) containing electrolytes and a solution (B-2) containing amino acids.
The present invention also provides a method for producing a solution containing a fat emulsion comprising coarsely emulsifying a fat using a high speed agitating homogenizer in the presence of saccharides and/or polyhydric alcohols, adding a water for injection and finely emulsifying the resultant coarse emulsion using a high pressure spray homogenizer under a pressure of 2000 to 3200 kgf/cm2 with a pass number through the homogenizer of 5 to 20 to obtain a fat emulsion consisting essentially of fat particles having a mean particle size of 0.003 to 0.100 xcexcm.